Macromolecular Structure
ABOUT
We use X-ray crystallography, in combination with other biophysical and biochemical approaches, to unveil two distinct biological problems: the molecular determinants of specific thrombin recognition and inhibition by natural anticoagulants from haematophagous animals, and the mechanism of action of unique enzymes from human pathogens, which are potential drug targets for therapeutic intervention.
RESEARCH
Our current research interests concentrate in two main lines:
1. The molecular mechanisms of specific thrombin recognition and inhibition by natural anticoagulants from haematophagous animals. In this field, our work contributed to unveiling the mode of action of several unique anticoagulants (e.g., boophilin from the cattle tick, anophelin from the malaria mosquito, and madanin and chimadanin from the bush tick). In the scope of a long-term collaboration with Richard Payne (University of Sydney, Australia) we also disclosed the dramatic effect of a specific post-translational modification, tyrosine sulfation, on inhibitor binding affinity;
2. The functional and structural characterization of novel potential drug targets from human pathogens. We have been devoting our attention to a unique biosynthetic mycobacterial pathway, leading to the production of complex polysaccharides. In close collaboration with Nuno Empadinhas (CNBC, Portugal), we have identified and characterized functional and structurally several of the intervening enzymes, unveiling their molecular determinants of substrate specificity.
Team
Selected Publications
Isolation, cloning and structural characterization of boophilin, a multifunctional Kunitz-type proteinase inhibitor from the cattle tick. PLoS ONE3(2):1-17, 2008. [Journal: Article] [CI: 101]
DOI: 10.1371/journal.pone.0001624 SCOPUS: 45849130590
Figueiredo A.C., De Sanctis D., Gutiérrez-Gallego R., Cereija T.B., Macedo-Ribeiro S., Fuentes-Prior P., Pereira P.J.B.,
Unique thrombin inhibition mechanism by anophelin, an anticoagulant from the malaria vector. Proceedings of the National Academy of Sciences of the United States of America109(52):, 2012. [Journal: Article] [CI: 47] [IF: 9,7]
DOI: 10.1073/pnas.1211614109 SCOPUS: 84871839379
Santos J.A., Alonso-Garciá N., Macedo-Ribeiro S., Barbosa Pereira P.J.,
The unique regulation of iron-sulfur cluster biogenesis in a Gram-positive bacterium. Proceedings of the National Academy of Sciences of the United States of America111(22):, 2014. [Journal: Article] [CI: 31] [IF: 9,7]
DOI: 10.1073/pnas.1322728111 SCOPUS: 84901821729
Torreira E., Seabra A.R., Marriott H., Zhou M., Llorca O., Robinson C.V., Carvalho H.G., Fernández-Tornero C., Pereira P.J.B.,
The structures of cytosolic and plastid-located glutamine synthetases from Medicago truncatula reveal a common and dynamic architecture. Acta Crystallographica Section D: Biological Crystallography70(4):981-993, 2014. [Journal: Article] [CI: 25] [IF: 2,7]
DOI: 10.1107/S1399004713034718 SCOPUS: 84898762319
Thompson R.E., Liu X., Ripoll-Rozada J., Alonso-García N., Parker B.L., Pereira P.J.B., Payne R.J.,
Tyrosine sulfation modulates activity of tick-derived thrombin inhibitors. Nature Chemistry9(9):909-917, 2017. [Journal: Article] [CI: 66] [IF: 26,2]
DOI: 10.1038/NCHEM.2744 SCOPUS: 85028339870
Ripoll-Rozada J., Costa M., Manso J.A., Maranha A., Miranda V., Sequeira A., Rita Ventura M., Macedo-Ribeiro S., Pereira P.J.B., Empadinhas N.,
Biosynthesis of mycobacterial methylmannose polysaccharides requires a unique 1-O-methyltransferase specific for 3-O-methylated mannosides. Proceedings of the National Academy of Sciences of the United States of America116(3):835-844, 2019. [Journal: Article] [CI: 6] [IF: 9,4]
DOI: 10.1073/pnas.1813450116 SCOPUS: 85060031004
Manso J.A., Nunes-Costa D., Macedo-Ribeiro S., Empadinhas N., Pereira P.J.B.,
Molecular fingerprints for a novel enzyme family in actinobacteria with glucosamine kinase activity. mBio10(3):, 2019. [Journal: Article] [CI: 2] [IF: 6,8]
DOI: 10.1128/mBio.00239-19 SCOPUS: 85066245592
Cereija T.B., Alarico S., Lourenço E.C., Manso J.A., Ventura M.R., Empadinhas N., Macedo-Ribeiro S., Pereira P.J.B.,
The structural characterization of a glucosylglycerate hydrolase provides insights into the molecular mechanism of mycobacterial recovery from nitrogen starvation. IUCrJ6:572-585, 2019. [Journal: Article] [CI: 2] [IF: 5,4]
DOI: 10.1107/S2052252519005372 SCOPUS: 85068320597
Hatos A., Hajdu-Soltész B., Monzon A.M., Palopoli N., Álvarez L., Aykac-Fas B., Bassot C., Benítez G.I., Bevilacqua M., Chasapi A., Chemes L., Davey N.E., Davidovic R., Dunker A.K., Elofsson A., Gobeill J., Foutel N.S.G., Sudha G., Guharoy M., Horvath T., Iglesias V., Kajava A.V., Kovacs O.P., Lamb J., Lambrughi M., Lazar T., Leclercq J.Y., Leonardi E., MacEdo-Ribeiro S., MacOssay-Castillo M., Maiani E., Manso J.A., Marino-Buslje C., Martínez-Pérez E., Mészáros B., Micetic I., Minervini G., Murvai N., Necci M., Ouzounis C.A., Pajkos M., Paladin L., Pancsa R., Papaleo E., Parisi G., Pasche E., Barbosa Pereira P.J., Promponas V.J., Pujols J., Quaglia F., Ruch P., Salvatore M., Schad E., Szabo B., Szaniszló T., Tamana S., Tantos A., Veljkovic N., Ventura S., Vranken W., Dosztányi Z., Tompa P., Tosatto S.C.E., Piovesan D.,
DisProt: Intrinsic protein disorder annotation in 2020. Nucleic Acids Research48(D1):D269-D276, 2020. [Journal: Article] [CI: 175] [IF: 17]
DOI: 10.1093/nar/gkz975 SCOPUS: 85077666918
Agten S.M., Watson E.E., Ripoll-Rozada J., Dowman L.J., Wu M.C.L., Alwis I., Jackson S.P., Pereira P.J.B., Payne R.J.,
Potent Trivalent Inhibitors of Thrombin through Hybridization of Salivary Sulfopeptides from Hematophagous Arthropods. Angewandte Chemie - International Edition60(10):5348-5356, 2021. [Journal: Article] [CI: 8] [IF: 16,8]
DOI: 10.1002/anie.202015127 SCOPUS: 85099868534
Calisto B.M., Ripoll-Rozada J., Dowman L.J., Franck C., Agten S.M., Parker B.L., Veloso R.C., Vale N., Gomes P., de Sanctis D., Payne R.J., Pereira P.J.B.,
Sulfotyrosine-Mediated Recognition of Human Thrombin by a Tsetse Fly Anticoagulant Mimics Physiological Substrates. Cell chemical biology28(1):26-33.e8, 2021. [Journal: Article] [CI: 12] [IF: 9]
DOI: 10.1016/j.chembiol.2020.10.002 SCOPUS: 85097103852